Structure-activity relation of NH2-terminal human parathyroid hormone fragments.
Human parathyroid hormone (hPTH) is involved in the regulation of the calcium level in blood. This hormone function is located in the NH2-terminal 34 amino acids of the 84-amino acid peptide hormone and is transduced via the adenylate cyclase and the phosphatidylinositol signaling pathways. It is well known that truncation of the two NH2-terminal amino acids of the hormone leads to complete loss of in vivo normocalcemic function. To correlate loss of calcium level regulatory activity after stepwise NH2-terminal truncation and solution structure, we studied the conformations of fragments hPTH-(2-37), hPTH-(3-37), and hPTH-(4-37) in comparison to hPTH-(1-37) in aqueous buffer solution under near physiological conditions by circular dichroism spectroscopy, two-dimensional nuclear magnetic resonance spectroscopy, and restrained molecular dynamics calculations. All peptides show helical structures and hydrophobic interactions between Leu-15 and Trp-23 that lead to a defined loop region from His-14 to Ser-17. A COOH-terminal helix from Met-18 to at least Leu-28 was found for all peptides. The helical structure in the NH2-terminal part of the peptides was lost in parallel with the NH2-terminal truncation and can be correlated with the loss of calcium regulatory activity.
Marx
U C
UC
Lehrstuhl für Biopolymere, Universität Bayreuth, D-95440 Bayreuth, Federal Republic of Germany.
Adermann
K
K
Bayer
P
P
Meyer
M
M
Forssmann
W G
WG
Rösch
P
P
D000595:Amino Acid Sequence; D000818:Animals; D002645:Chickens; D002942:Circular Dichroism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010281:Parathyroid Hormone / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D051381:Rats; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D010281:Parathyroid Hormone; D010446:Peptide Fragments